PDF(Pubmed)
Abstract：
Lung cancer is the leading cause of cancer-related deaths. Lung cancer cells develop resistance to apoptosis by suppressing the secretion of the tumor suppressor Par-4 protein (also known as PAWR) and/or down-modulating the Par-4 receptor GRP78 on the cell surface (csGRP78). We sought to identify FDA-approved drugs that elevate csGRP78 on the surface of lung cancer cells and induce Par-4 secretion from the cancer cells and/or normal cells in order to inhibit cancer growth in an autocrine or paracrine manner. In an unbiased screen, we identified crizotinib (CZT), an inhibitor of activated ALK/MET/ROS1 receptor tyrosine kinase, as an inducer of csGRP78 expression in ALK-negative, KRAS or EGFR mutant lung cancer cells. Elevation of csGRP78 in the lung cancer cells was dependent on activation of the non-receptor tyrosine kinase SRC by CZT. Inhibition of SRC activation in the cancer cells prevented csGRP78 translocation but promoted Par-4 secretion by CZT, implying that activated SRC prevented Par-4 secretion. In normal cells, CZT did not activate SRC and csGRP78 elevation but induced Par-4 secretion. Consequently, CZT induced Par-4 secretion from normal cells and elevated csGRP78 in the ALK-negative tumor cells to cause paracrine apoptosis in cancer cell cultures and growth inhibition of tumor xenografts in mice. Thus, CZT induces differential activation of SRC in normal and cancer cells to trigger the pro-apoptotic Par-4-GRP78 axis. As csGRP78 is a targetable receptor, CZT can be repurposed to elevate csGRP78 for inhibition of ALK-negative lung tumors.
摘要：
肺癌是癌症相关死亡的主要原因。肺癌细胞通过抑制肿瘤抑制因子Par-4蛋白(也称为PAWR)的分泌和/或下调细胞表面上的Par-4受体GRP78(cGRsP78)来发展对凋亡的抗性。我们试图鉴定FDA批准的药物，这些药物可以提高肺癌细胞表面的csGRP78并诱导癌细胞和/或正常细胞的Par-4分泌，从而以自分泌或旁分泌的方式抑制癌症生长。在一个不偏不倚的屏幕上，我们确定了克唑替尼（CZT），激活的ALK/MET/ROS1受体酪氨酸激酶的抑制剂，作为CSGRP78在ALK阴性表达的诱导剂，KRAS或EGFR突变肺癌细胞。肺癌细胞中csGRP78的升高依赖于CZT对非受体酪氨酸激酶SRC的激活。抑制癌细胞中的SRC激活可防止csGRP78易位，但可促进CZT分泌Par-4，这意味着激活的SRC阻止了Par-4的分泌。在正常细胞中,CZT不会激活SRC和csGRP78升高，但会诱导Par-4分泌。因此,CZT诱导正常细胞分泌Par-4，并在ALK阴性肿瘤细胞中升高csGRP78，从而引起癌细胞培养物中的旁分泌凋亡和小鼠肿瘤异种移植物的生长抑制。因此，CZT诱导正常细胞和癌细胞中SRC的差异激活以触发促凋亡Par-4-GRP78轴。由于csGRP78是一种可靶向受体，CZT可用于提高csGRP78以抑制ALK阴性肺肿瘤。
